Estrogens have well-documented effects on the survival and growth of target neurons in various regions of the mammalian brain. In the adult and aged brain, estrogen may be trophic to and/or protect from damage neuronal populations important in cognition such as the basal forebrain cholinergic system. Aging in both the male and female is associated with a decline in the secretion of estrogens and androgens and it is possible that this decline could have implications for aging of brain neurons. Whether effects of this type occur in the human brain are unknown, but interesting reports have suggested that estrogen treatment improves condition in young and elderly women and that the incidence of Alzheimer's disease in estrogen-replaced in postmenopausal women is much lower than in women not given this treatment. Neuronal development appears to be in large part dependent upon the actions of neurotrophins such as nerve growth acting through tyrosine kinase receptors, specifically trk A and p75. We have recently reported that estrogen and certain agents termed selective estrogen receptor modulators (SERMs) can discretely activate certain of the downstream signal transduction cascades used by growth factors such as the MAP-Kinase pathway. In the present application, we propose to develop primary cultures and human neuronal cell-line models in which to evaluate further the neuroprotective effects of estrogen and its interaction with neurotrophin and MAP kinase-related signaling mechanisms. Specific Aim 1: To assess the neuroprotective effects of estrogen, SERMs, and ER-beta selective phytoestrogens in primary neuronal cultures. Specific Aim 2. To identify the signal transduction events which mediate the neuroprotective effects of estrogens in primary neuronal cultures. Specific Aim 3. To identify structural features of the estrogen receptors alpha and beta and the proteins which they interact to mediate neuroprotection in transfected cell systems. Specific aim 4. To investigate the ability of estrogen to induce neuroprotective genes such as Bcl-2 in human NT2N neurons.